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Bernhard LuscherRegulation of GABA-A receptor trafficking and inhibitory synapse formation by palmitoylation

Abstract :

Synaptic transmission by gamma-aminobutyric acid (GABA) is vital for normal brain function. This is evidenced by the contribution of GABAergic deficits to the etiology of a wide range of devastating neurological and psychiatric disorders including epilepsy, anxiety and mood disorders, and schizophrenia. Deficits in GABAergic transmission may reflect deficits in GABAergic innervation or in the expression, cellular distribution, or function of GABAA receptors (GABA-ARs). I will focus on palmitoylation as a critically important posttranslational modification that regulates the postsynaptic differentiation of GABAergic synapses, and thereby also controls GABAergic innervation. The gamma 2 subunit is an essential determinant of postsynaptic accumulation of GABA-ARs. We have found that the gamma2 subunit of GABA-ARs and the inhibitory synapse-specific cell adhesion molecule neuroligin-2 (NL2) are palmitoylated in vitro with striking selectivity by the same two closely related DHHC-type palmitoyltransferases (PATs), GODZ and SERZ-beta. I will present evidence for a mechanism whereby palmitoylation of NL2 and GABA-ARs ensures the faithful accumulation of GABA-ARs at inhibitory as opposed to excitatory synapses.

Selected publications

Yuan X., J. Yao, J.S. Qi, D. Norris, D.D. Tran, R.J. Bram, G. Chen and B. Luscher (2008) Calcium-Modulating cyclophilin Ligand regulates membrane trafficking of postsynaptic GABA-A receptors. Mol. Cell. Neurosci., in press.    
Deng L., J. Yao, C. Fang, N. Dong, B. Luscher and G. Chen (2007). Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures. J. Neurosci. 27, 10860-1086. (pdf file)
Earnheart J.C., C. Schweizer, F. Crestani, T. Iwasato, S. Itohara, H. Mohler, and B. Luscher (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J. Neurosci. 27, 3845-3854. (pdf file)